Vanilloid receptor 1 (VR1) is a ligand gated non-selective cation channel. It is believed to be a member of the transient receptor potential super family. VR1 is recognized as a polymodal nociceptor that integrates multiple pain stimuli, e.g., noxious heat, protons, and vanilloids. A major distribution of VR1 is in the sensory (Aδ- and C-) fibers, which are bipolar neurons having somata in sensory ganglia. The peripheral fibers of these neurons innervate the skin, the mucosal membranes, and almost all internal organs. It is also recognized that VR1 exists in bladder, kidney, brain, pancreas, and various kinds of organs. A body of studies using VR1 agonists, e.g., capsaicin or resiniferatoxin, have suggested that VR1 positive nerves are thought to participate in a variety of physiological responses, including nociception. Based on both the tissue distribution and the roles of VR1, VR1 antagonists would have good therapeutic potential.
WO200216318A1 discusses N-sulfonylaminobenzyl-3-propionamide derivatives as a modulator for vanilloid receptor. However, the specification of WO200216318A1 is silence about the compounds having an oxygen atom as part of the amide linker between two phenyl groups.
WO200216319A1 discusses methansulfonylaminophenyl acetid acid derivatives as a modulator for vanilloid receptor. With respect to the order of NH and carbonyl groups in the linker between two phenyl groups, the compounds in WO200216319A1 is reverse to the compounds of the present invention. Further WO200216319A1 is silence about the compounds having an oxygen atom as part of the amide linker between two phenyl groups.
WO2005003084A1, published on Jan. 13, 2005 (after the first priority date of the present application of Nov. 11, 2004), discusses 4-(methylsulfonylamino)phenyl analogues as a vanilloid antagonist. However, in WO2005003084, there is no concrete description about phenoxy acetatamide compounds such as the compounds of the present invention. Also there is no description, suggestion or motivation about introducing an alkyl group to the phenyl group substituted with an alkylsulfonylamino group, or about compounds having a methylene group next to the phenyl group substituted with an alkylsulfonylamino group.
Further, the compounds of the present invention possess an excellent compound series in a human VR1 antagonist activitiy by introducing an oxygen atom into the linker. Further the compounds of the present invention also possess an excellent half-life value by introducing an oxygen atom into the linker, being substituted with an alkyl group to the phenyl group having an alkylsulfonylamino group and/or having a methylene group, as part of the linker, next to the phenyl group substituted with an alkylsulfonylamino group.
It would be desirable if there were provided a novel VR1 selective antagonist with potent binding activity with VR1 receptor by systemic administration, and both with less toxicity, good absorption, good half-life, good solubility, low protein binding affinity, less drug-drug interaction, a reduced inhibitory activity at HERG channel, reduced QT prolongation and good metabolic stability.